title: A novel copper complex induces paraptosis in colon cancer cells via the activation of ER stress signalling.
abstract: Platinum anticancer drugs have been used for three decades despite their serious side effects and the emerging of resistance phenomena. Recently, a phosphine copper(I) complex, [Cu(thp)(4)][PF(6)] (CP), gained special attention because of its strong antiproliferative effects. CP killed human colon cancer cells more efficiently than cisplatin and oxaliplatin and it overcame platinum drug resistance. CP preferentially reduced cancer cell viability whereas non-tumour cells were poorly affected. Colon cancer cells died via a programmed cell death whose transduction pathways were characterized by the absence of hallmarks of apoptosis. The inhibition of 26S proteasome activities induced by CP caused intracellular accumulation of polyubiquitinated proteins and the functional suppression of the ubiquitin-proteasome pathway thus triggering endoplasmic reticulum stress. These data, providing a mechanistic characterization of CP-induced cancer cell death, shed light on the signaling pathways involved in paraptosis thus offering a new tool to overcome apoptosis-resistance in colon cancer cells.
authors.affiliation: Department of Pharmaceutical Sciences, University of Padova, Padova, Italy. valentina.gandin@unipd.it
authors.forename: Valentina
authors.initials: V
authors.lastname: Gandin
authors.forename: Maura
authors.initials: M
authors.lastname: Pellei
authors.forename: Francesco
authors.initials: F
authors.lastname: Tisato
authors.forename: Marina
authors.initials: M
authors.lastname: Porchia
authors.forename: Carlo
authors.initials: C
authors.lastname: Santini
authors.forename: Cristina
authors.initials: C
authors.lastname: Marzano
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor / Q000187:drug effects / Q000648:ultrastructure; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D003300:Copper / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006801:Humans; D015394:Molecular Structure; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D003300:Copper